1. Field of the Invention
The invention relates to lipoxin A4 analogs, their use in treating inflammatory and autoimmune disorders and pulmonary and respiratory tract inflammation, and pharmaceutical compositions containing the analogs and processes for their preparation.
2. Background of the Invention
Lipoxins, together with leukotrienes, prostaglandins, and thromboxanes, constitute a group of biologically active oxygenated fatty acids collectively referred to as the eicosanoids. Eicosanoids are all synthesised de novo from membrane phospholipid via the arachidonic acid cascade of enzymes. Since their initial discovery in 1984, it has become apparent that lipoxins, which are a structurally unique class of eicosanoids, possess potent anti-inflammatory properties that suggest they may have therapeutic potential (Serhan, C. N., Prostaglandins (1997), Vol. 53, pp. 107-137; O'Meara, Y. M. et al., Kidney Int. (Suppl.) (1997), Vol. 58, pp. S56-S61; Brady, H. R. et al., Curr. Opin. Nephrol. Hypertens. (1996), Vol. 5, pp. 20-27; and Serhan, C. N., Biochem. Biophys. Acta. (1994), Vol. 1212, pp. 1-25). Of particular interest is the ability of lipoxins to antagonize the pro-inflammatory functions of leukotrienes in addition to other inflammatory agents such as platelet activating factor, FMLP, immune complexes and TNFα. Lipoxins are thus potent anti-neutrophil (PMN) agents which inhibit PMN chemotaxis, homotypic aggregation, adhesion, migration across endothelial and epithelial cells, margination/diapedesis and tissue infiltration (Lee, T. H., et al., Clin. Sci. (1989), Vol. 77, pp. 195-203; Fiore, S., et al., Biochemistry (1995), Vol. 34, pp. 16678-16686; Papyianni, A., et al., J. Immunol. (1996), Vol. 56, pp. 2264-2272; Hedqvist, P., et al., Acta. Physiol. Scand. (1989), Vol. 137, pp. 157-572; Papyianni, A., et al., Kidney Intl. (1995), Vol. 47, pp. 1295-1302). In addition, lipoxins are able to down-regulate endothelial P-selectin expression and adhesiveness for PMNs (Papyianni, A., et al., J. Immunol. (1996), Vol. 56, pp. 2264-2272), bronchial and vascular smooth muscle contraction, mesangial cell contraction and adhesiveness (Dahlen, S. E., et al., Adv. Exp. Med. Biol. (1988), Vo. 229, pp. 107-130; Christie, P. E., et al., Am. Rev. Respir. Dis. (1992), Vol. 145, pp. 1281-1284; Badr, K. F., et al., Proc. Natl. Acad. Sci. (1989), Vol. 86, pp. 3438-3442; and Brady, H. R., et al., Am. J. Physiol. (1990), Vol. 259, pp. F809-F815) and eosinophil chemotaxis and degranulation (Soyombo, O., et al., Allergy (1994), Vol. 49, pp. 230-234).
This unique anti-inflammatory profile of lipoxins, particularly lipoxin A4, has prompted interest in exploiting their potential as therapeutics for the treatment of inflammatory or autoimmune disorders and pulmonary and respiratory tract inflammation. Such disorders and inflammation which exhibit a pronounced inflammatory infiltrate are of particular interest and include dermatologic diseases, such as psoriasis, and rheumatoid arthritis, and respiratory disorders, such as asthma.
As with other endogenous eicosanoids, naturally occurring lipoxins are unstable products which are rapidly metabolized and inactivated (Serhan, C. N., Prostaglandins (1997), Vol. 53, pp. 107-137). This has limited the development of the lipoxin field of research, particularly with respect to in vivo pharmacological assessment of the anti-inflammatory profile of lipoxins. Several U.S. Patents have issued directed to compounds having the active site of lipoxin A4, but with a longer tissue half-life. See, e.g., U.S. Pat. Nos. 5,441,951 and 5,648,512, the disclosures of which are incorporated in full by reference herein. These compounds retain lipoxin A4 receptor binding activity and the potent in vitro and in vivo anti-inflammatory properties of natural lipoxins (Takano, T., et al., J. Clin. Invest. (1998), Vol. 101, pp. 819-826; Scalia, R., et al., Proc. Natl. Acad. Sci. (1997), Vol. 94, pp. 9967-9972; Takano, T., et al., J. Exp. Med. (1997), Vol. 185, pp. 1693-1704; Maddox, J. F., et al., J. Biol. Chem. (1997), Vol. 272, pp. 6972-6978; Serhan, C. N., et al., Biochemistry (1995), Vol. 34, pp. 14609-14615).
All of the references cited herein, including published patent applications and journal articles, are incorporated in full by reference herein.